Compositions and methods for treatment of mitochondrial diseases

Abstract

Compounds, compositions, and methods are provided for treatment of disorders related to mitochondrial dysfunction. The methods comprise administering to a mammal a composition containing pyrimidine nucleotide precursors in amounts sufficient to treat symptoms resulting from mitochondrial respiratory chain deficiencies.

1 - 46 . (canceled)  
     
     
         47 . A method for treating or preventing pathophysiological consequences of mitochondrial respiratory chain dysfunction in a mammal comprising administering to said mammal in need of such treatment or prevention an effective amount of a pyrimidine nucleotide precursor.  
     
     
         48 . A method as in  claim 47  wherein said respiratory chain dysfunction is caused by a mutation, deletion, or rearrangement of mitochondrial DNA.  
     
     
         49 . A method as in  claim 47  wherein said respiratory chain dysfunction is caused by defective nuclear-encoded protein components of the mitochondrial respiratory chain.  
     
     
         50 . A method as in  claim 47  wherein said respiratory chain dysfunction is caused by aging.  
     
     
         51 . A method as in  claim 47  wherein said respiratory chain dysfunction is caused by administration of cytotoxic cancer chemotherapy agents to said mammal.  
     
     
         52 . A method as in  claim 47  wherein said respiratory chain dysfunction is a deficit in mitochondrial Complex I activity.  
     
     
         53 . A method as in  claim 47  wherein said respiratory chain dysfunction is a deficit in mitochondrial Complex II activity.  
     
     
         54 . A method as in  claim 47  wherein said respiratory chain dysfunction is a deficit in mitochondrial Complex III activity.  
     
     
         55 . A method as in  claim 47  wherein said respiratory chain dysfunction is a deficit in mitochondrial Complex IV activity.  
     
     
         56 . A method as in  claim 47  wherein said respiratory chain dysfunction is a deficit in mitochondrial Complex V activity.  
     
     
         57 . A method as in  claim 47  wherein said pyrimidine nucleotide precursor is selected from the group consisting of uridine, cytidine, an acyl derivative of uridine, an acyl derivative of cytidine, orotic acid, an alcohol ester of orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         58 . A method as in  claim 57  wherein said pyrimidine nucleotide precursor is an acyl derivative of cytidine.  
     
     
         59 . A method as in  claim 57  wherein said pyrimidine nucleotide precursor is an acyl derivative of uridine.  
     
     
         60 . A method as in  claim 57  wherein said acyl derivative of uridine is 2′, 3′, 5′-tri-O-acetyluridine.  
     
     
         61 . A method as in  claim 57  wherein said acyl derivative of uridine is 2′, 3′, 5′-tri-O-pyruvyluridine.  
     
     
         62 . A method as in  claim 57  wherein the alcohol substituent of said alcohol ester of orotic acid is ethanol.  
     
     
         63 . A method as in  claim 57  wherein said pyrimidine nucleotide precursor is cytidine diphosphocholine.  
     
     
         64 . A method as in  claim 57  wherein said pyrimidine nucleotide precursor is administered orally.  
     
     
         65 . A method as in  claim 47  wherein said pathophysiological consequence of mitochondrial respiratory chain dysfunction is a congential mitochondrial disease.  
     
     
         66 . A method as in  claim 65  wherein said congenital mitochondrial disease is selected from the group consisting of MELAS, LHON, MERRF, NARP, PEO, Leigh's Disease, and Kearns-Sayres Syndrome.  
     
     
         67 . A method as in  claim 47  wherein said pathophysiological consequence of mitochondrial respiratory chain dysfunction is a neurodegenerative disease.  
     
     
         68 . A method as in  claim 67  wherein said neurodegenerative disorder is Alzheimer's Disease.  
     
     
         69 . A method as in  claim 67  wherein said neurodegenerative disorder is Parkinson's Disease.  
     
     
         70 . A method as in  claim 67  wherein said neurodegenerative disorder is Huntington's Disease.  
     
     
         71 . A method as in  claim 67  wherein said neurodegenerative disorder is age-related decline in cognitive function.  
     
     
         72 . A method as in  claim 47  wherein said pathophysiological consequence of mitochondrial respiratory chain dysfunction is a neuromuscular degenerative disease.  
     
     
         73 . A method as in  claim 72  wherein said neuromuscular degenerative disease is selected from the group consisting of muscular dystrophy, myotonic dystrophy, chronic fatigue syndrome, and Friedreich's Ataxia.  
     
     
         74 . A method as in  claim 47  wherein said pathophysiological consequence of mitochondrial respiratory chain dysfunction is developmental delay in cognitive, motor, language, executive function, or social skills.  
     
     
         75 . A method as in  claim 47  wherein said pathophysiological consequence of mitochondrial respiratory chain dysfunction is selected from the group consisting of epilepsy, peripheral neuropathy, optic neuropathy, autonomic neuropathy, neurogenic bowel dysfunction, sensorineural deafness, neurogenic bladder dysfunction, migraine, and ataxia.  
     
     
         76 . A method as in  claim 47  wherein said pathophysiological consequence of mitochondrial respiratory chain dysfunction is selected from the group consisting of renal tubular acidosis, dilating cardiomyopathy, hepatic failure, and lactic acidemia.  
     
     
         77 . A method for preventing death or functional decline of post-mitotic cells in a mammal due to mitochondrial respiratory chain dysfunction comprising administration of an effective amount of a pyrimidine nucleotide precursor.  
     
     
         78 . A method as in  claim 77  wherein said post-mitotic cells are neurons.  
     
     
         79 . A method as in  claim 77  wherein said post-mitotic cells are skeletal muscle cells.  
     
     
         80 . A method as in  claim 77  wherein said post-mitotic cells are cardiomyocytes.  
     
     
         81 . A method for treating developmental delay in cognitive, motor, language, executive function, or social skills in a mammal comprising administration of an effective amount of a pyrimidine nucleotide precursor.  
     
     
         82 . A method as in  claim 81  wherein said developmental delay is pervasive developmental delay or PPD-NOS.  
     
     
         83 . A method as in  claim 81  wherein said developmental delay is Attention Deficit/Hyperactivity Disorder.  
     
     
         84 . A method as in  claim 81  wherein said developmental delay is Rett's Syndrome.  
     
     
         85 . A method as in  claim 81  wherein said developmental delay is autism.  
     
     
         86 . A pharmaceutical composition comprising: 
 (a) a pyrimidine nucleotide precursor or a pharmaceutically acceptable salt thereof, and    (b) pyruvic acid, a pharmaceutically acceptable salt thereof, or a pyruvic acid ester.    
     
     
         87 . A method as in  claim 47  further comprising administering pyruvic acid, a pharmaceutically acceptable salt thereof, or a pyruvic acid ester.